The Legionella Effector Kinase LegK7 Hijacks the Host Hippo Pathway to Promote Infection

Cell Host Microbe. 2018 Sep 12;24(3):429-438.e6. doi: 10.1016/j.chom.2018.08.004.

Abstract

The intracellular pathogen Legionella pneumophila encodes translocated effector proteins that modify host cell processes to support bacterial survival and growth. Here, we show that the L. pneumophila effector protein LegK7 hijacks the conserved Hippo signaling pathway by molecularly mimicking host Hippo kinase (MST1 in mammals), which is the key regulator of pathway activation. LegK7, like Hippo/MST1, phosphorylates the scaffolding protein MOB1, which triggers a signaling cascade resulting in the degradation of the transcriptional regulators TAZ and YAP1. Transcriptome analysis revealed that LegK7-mediated targeting of TAZ and YAP1 alters the transcriptional profile of mammalian macrophages, a key cellular target of L. pneumophila infection. Specifically, genes targeted by the transcription factor PPARγ, which is regulated by TAZ, displayed altered expression, and continuous interference with PPARγ activity rendered macrophages less permissive to L. pneumophila intracellular growth. Thus, a conserved L. pneumophila effector kinase exploits the Hippo pathway to promote bacterial growth and infection.

Keywords: Hippo pathway; PPARγ; effectors; human proteome array; intracellular pathogens; kinases; thiophosphorylation.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Motifs
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Legionella pneumophila / chemistry
  • Legionella pneumophila / enzymology*
  • Legionella pneumophila / genetics
  • Legionella pneumophila / growth & development
  • Legionnaires' Disease / genetics
  • Legionnaires' Disease / metabolism*
  • Legionnaires' Disease / microbiology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • PPAR gamma
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport
  • Proteolysis
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Bacterial Proteins
  • Intracellular Signaling Peptides and Proteins
  • MOB1A protein, human
  • PPAR gamma
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Acyltransferases
  • TAFAZZIN protein, human
  • Protein Kinases
  • STK4 protein, human
  • Protein Serine-Threonine Kinases